Protein tyrosine-tyrosine analogs and methods of using the same

Abstract

PYY analogs are disclosed that include modifications that increase half-life when compared to native, human PYY, as well as additional modifications that increase potency and selectivity to the NPY2 receptor. Pharmaceutical compositions also are disclosed that include one or more of the PYY analogs described herein in a pharmaceutically acceptable carrier. Methods of making and using the PYY analogs also are disclosed, especially for treating obesity and obesity-related diseases and disorders such as type II diabetes mellitus.

The invention claimed is: 
     
       1. A Peptide Tyrosine-Tyrosine (PYY) analog comprising an amino acid sequence of:
   PKPEX 7 PX 9 X 10 DASPEEX 17 X 18 RYYX 22 X 23 LRHYLNX 30 LTRQRY  (Formula I),
 
 
       wherein X 7  is any amino acid with a functional group available for conjugation and the functional group is conjugated to a C 16 -C 22  fatty acid, wherein the C 16 -C 22  fatty acid is conjugated to the amino acid with the functional group available for conjugation via a linker, and wherein the linker can be one or more units selected from the group consisting of [2-(2-amino-ethoxy)-ethoxy)]-acetic acid (AEEA), aminohexanoic acid (Ahx), glutamic acid (E), gamma glutamic acid (γE) and combinations thereof,
 wherein X 9  is E or G, 
 wherein X 10  is E or K, 
 wherein X 17  is L or W, 
 wherein X 18  is N or Q, 
 wherein X 22  is A or I, 
 wherein X 23  is E, D or S, 
 wherein X 30  is E or W (SEQ ID NO:3), and 
 wherein a C-terminal amino acid is optionally amidated. 
 
     
     
       2. The PYY analog of  claim 1 , wherein X 7  is selected from the group consisting of C, D, E, K and Q. 
     
     
       3. The PYY analog of  claim 1 , wherein X 7  is K and conjugation to the C 16 -C 22  fatty acid is through an epsilon-amino group of a K side chain. 
     
     
       4. The PYY analog of  claim 1 , wherein the amino acid sequence is selected from the group consisting of:
 PKPEKPGEDASPEEWQRYYAELRHYLNWLTRQRY (SEQ ID NO:4); 
 PKPEKPGEDASPEEWQRYYAELRHYLNELTRQRY (SEQ ID NO:5); 
 PKPEKPEEDASPEEWQRYYIELRHYLNWLTRQRY (SEQ ID NO:6); 
 PKPEKPGKDASPEEWNRYYADLRHYLNWLTRQRY (SEQ ID NO:7); and 
 PKPEKPGEDASPEELQRYYASLRHYLNWLTRQRY (SEQ ID NO:8). 
 
     
     
       5. The PYY analog of  claim 1 , wherein the C 16 -C 22  fatty acid is selected from the group consisting of a hexadecanoic acid, a hexadecanedioic acid, a heptadecanoic acid, a heptadecanedioic acid, a stearic acid, an octadecanedioic acid, a nonadecylic acid, a nonadecanedioic acid, an eicosanoic acid, an eicosanedioic acid, a heneicosanoic acid, a heneicosanedioic acid, a docosanoic acid, a docosanedioic acid, and branched and substituted derivatives thereof. 
     
     
       6. The PYY analog of  claim 5 , wherein the C 16 -C 22  fatty acid is a C 18 -C 20  fatty acid. 
     
     
       7. The PYY analog of  claim 6 , wherein the C 18 -C 20  fatty acid is a straight-chain fatty acid having a formula of CO—(CH 2 ) x —CO 2 H, and wherein x is 16 or 18. 
     
     
       8. The PYY analog of  claim 7 , wherein the C 18 -C 20  fatty acid is selected from the group consisting of palmitic acid, stearic acid, arachidic acid and eicosanoic acid. 
     
     
       9. The PYY analog of  claim 1 , wherein the amino acid sequence is: 
       
         
           
           
               
               
           
         
       
     
     
       10. The PYY analog of  claim 1 , wherein the amino acid sequence is: 
       
         
           
           
               
               
           
         
       
     
     
       11. The PYY analog of  claim 1 , wherein the amino acid sequence is: 
       
         
           
           
               
               
           
         
       
     
     
       12. The PYY analog of  claim 1 , wherein the amino acid sequence is: 
       
         
           
           
               
               
           
         
       
     
     
       13. The PYY analog of  claim 1 , wherein the amino acid sequence is: 
       
         
           
           
               
               
           
         
       
     
     
       14. The PYY analog of  claim 1 , wherein the linker and the fatty acid together are selected from the group consisting of (AEEA) 2 ·γE·C 20  diacid, Ahx·E·γE·C 18  diacid, and AEEA·γE·C 18  diacid. 
     
     
       15. A pharmaceutical composition comprising:
 at least one Peptide Tyrosine-Tyrosine (PYY) analog of  claim 1  or a salt thereof; and 
 one or more pharmaceutically acceptable carriers, diluents and excipients. 
 
     
     
       16. The pharmaceutical composition of  claim 15  further comprising an additional therapeutic agent. 
     
     
       17. The pharmaceutical composition of  claim 16 , wherein the additional therapeutic agent is an incretin selected from the group consisting of glucagon (GCG), a GCG analog, glucagon-like peptide-1 (GLP-1), GLP-1 7-36-amide , a GLP-1 analog, gastric inhibitory peptide (GIP), a GIP analog, oxyntomodulin (OXM), an OXM analog, a GIP/GLP-1, a GLP-1/GCG, or an incretin analog having triple receptor activity. 
     
     
       18. The pharmaceutical composition of  claim 16 , wherein the additional therapeutic agent is a dipeptidyl peptidase-IV (DPP-IV) inhibitor. 
     
     
       19. The PYY analog of  claim 18 , wherein the (AEEA) 2 ·γE·C 20  diacid is (AEEA) 2 -(γE)-CO—(CH 2 ) 18 —COOH, wherein the Ahx·E·γE·C 18  diacid is (Ahx-E-(γE)-CO—(CH 2 ) 16 —COOH, and wherein the AEEA·γE·C 18  diacid is (AEEA)-(γE)-CO—(CH 2 ) 16 —COOH. 
     
     
       20. A method of treating obesity or an obesity related disease or disorder, the method comprising a step of:
 administering to an individual in need thereof an effective amount of a Peptide Tyrosine-Tyrosine (PYY) analog of  claim 1  or a pharmaceutically acceptable salt thereof. 
 
     
     
       21. The method of  claim 20 , wherein the PYY analog or pharmaceutically acceptable salt thereof is subcutaneously (SQ) administered to the individual. 
     
     
       22. The method of  claim 20 , where the PYY analog or pharmaceutically acceptable salt thereof is orally administered to the individual. 
     
     
       23. The method of  claim 20 , wherein the PYY analog or pharmaceutically acceptable salt thereof is administered daily, every other day, three times a week, two times a week, one time a week, or biweekly. 
     
     
       24. The method of  claim 20 , wherein the PYY analog or pharmaceutically acceptable salt thereof is administered SQ one time a week (QW). 
     
     
       25. The method of  claim 20 , wherein the PYY analog or pharmaceutically acceptable salt thereof is administered orally one time a week. 
     
     
       26. The method of  claim 20  further comprising administering an additional therapeutic agent. 
     
     
       27. The method of  claim 26 , wherein the additional therapeutic agent is an incretin selected from the group consisting of glucagon (GCG), a GCG analog, glucagon-like peptide-1 (GLP-1), GLP-1 7-36-amide , a GLP-1 analog, gastric inhibitory peptide (GIP), a GIP analog, oxyntomodulin (OXM), an OXM analog, a GIP/GLP-1, a GLP-1/GCG, or an incretin analog having triple receptor activity. 
     
     
       28. The method of  claim 26 , wherein the additional therapeutic agent is a dipeptidyl peptidase-IV (DPP-IV) inhibitor.